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Structural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib

Zhipeng Xie1, Jiaxiang Lv1, Wei Huang1

  • 1Department of Neurosurgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.

Cell Reports
|March 26, 2025
PubMed

Insights

Lapatinib overcomes multidrug resistance (MDR) by inhibiting human MRP4 (hMRP4), a key protein in chemotherapy resistance. Structural studies reveal lapatinib

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Multidrug resistance proteins (MRPs) are crucial in cancer chemotherapy failure.
  • Human MRP4 (hMRP4) contributes to resistance against various anticancer drugs.

Purpose of the Study:

  • To elucidate the mechanism of hMRP4-mediated drug resistance.
  • To investigate the role of lapatinib in overcoming hMRP4-mediated resistance.
  • To determine the structural basis of hMRP4 inhibition by lapatinib.

Main Methods:

  • Cell culture and drug resistance assays.
  • Cryo-electron microscopy (cryo-EM) for structural determination.
  • Biochemical binding assays.

Main Results:

  • hMRP4 mediates resistance to vincristine and 5-fluorouracil.
  • Lapatinib rescues sensitivity to these drugs by inhibiting hMRP4.
  • Cryo-EM structures reveal lapatinib's high affinity and unique binding mode within hMRP4.
  • Lapatinib prevents hMRP4 conformational changes essential for drug efflux.

Conclusions:

  • Lapatinib effectively inhibits hMRP4, offering a strategy against MDR.
  • Structural insights explain lapatinib's potent inhibition of hMRP4.
  • Targeting hMRP4 with lapatinib holds therapeutic potential for resistant cancers.
Keywords:
ABCC4CP: Molecular biologyMRP4MRP4 inhibitorscryo-EM structuresinhibition mechanismlapatinibmultidrug resistance proteinsreversal of drug resistance

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